A drug company from Quebec has developped a new drug that targets RNA, and which was specifically designed to inhibit the recruitment and survival of eosinophils as well as the release of associated cytokines. Named TPI ASM8, it combines 2 modified oligodeoxynucleotides : ODN (phosphorothioates TOP 004 and TOP005) which, by acting as reverse transcriptases (antisense), block the CCR3 chemokine and the β (βc) sub-unit which is shared by receptors for Interleukins IL-3, IL-5 and GM-CSF.
This innovative product is administered by inhaled route and has thus few systemic effects. It is currently still in a phase II, randomised multicentre study, but the first results have been the subject of a preliminary publication (Antisense therapy against CCR3 and the common βchain attenuates allergen induced response . G.M.Gauvreau et al Am.J. Resp.Crit.Care Med 2008 January 31 ahead of print).
In this study, 17 with moderate asthma, off corticosteroids for at least one month, were treated with 1500mcg of the drug once daily for 4 days : on the 3rd day they were exposed to the allergen that is responsible for their asthma symptoms ( cat, in 9 cases, house dust mite, in 6 cases, and pollens in 2 cases : grass and birch) . Sputum was collected before and after the provocation test. Levels of expression of CCR3 βc protein were measured by flow cytometry, mRNA was measured by real time PCR, and VEMS was measured during and 7 hours after the provocation test. Compared to placebo, Topigen ® (not yet commercialised in Europe) was associated with a 46% inhibition of eosinophil influx (p=0.02) as well as with inhibition of cell growth (63%).
It greatly reduced immediate, early bronchospasm upon bronchial allergen challenge (p=0.03) and also more moderately reduced the late bronchial reaction (p=0.08)
Topigen also inhibited expression of mRNA for βc and CCR3 in sputum cells (p=0.039 and p=0.055, respectively). The drug was very well clinically and biologically tolerated.
Thus, TPI ASM8 attenuated allergen challenge-associated bronchial responses and increased expression of target RNA. This is the first clinical trial using anti-sense ODN administered locally, thereby allowing us to foresee future treatments that may inhibit expression of multiple genes.
There are 3 types of pesticides : Insecticides, Herbicides and Fungicides. In a recent american study that included an epidemiological survey performed between 1993 and 1997 in 25.814 female farmers (Pesticides and Atopic and Nonatopic asthma among farm women : .J.A.Hoppin et al.. Am.J.Resp. Crit. Care Med 2008 177 11-18) the authors had the double opportunity to analyse the well known protective role of a rural environment against atopy and asthma as well as the deleterious effect the same environment can have, in terms of ocupational exposure, upon the respiratory system.
In this group, some of the women had been born and been raised on a farm. Others had married farmers as adults and were exposed to the various rural pollutants, by participating, to a higher or lesser degree, in daily rural chores.
The authors studied the frequency of atopic and non atopic as well as the role of pesticides in each category in this population.
702 patients became asthmatic after the age of 19 (282 atopic and 420 non atopic) : the study confirmed that growing up in a rural environment significantly protects against atopic Asthma In contrast, the utilisation of these products (by 57% of female farmers) was nearly exclusively associated with atopic Asthma .
7 of the 16 Insecticides (Organophosphates, Malathion, DDT, Lindane), 2 of the 11 Herbicides (Aryloxacide and Phytohormone family) and 1 of the 4 Fungicides (Maneb) were particularly associated with atopic Asthma .
Only the insecticide Permethrin was associated with non atopic Asthma .
This work thus confirms hygiene hypothesis for Allergy and Asthma, and the protective role of living at young age in a rural environment but also stresses the noxious effect of Pesticides on the respiratory system and, above all of the Insecticides, in the development of, among others, noxious respiratory effects and atopic Asthma .
Angioedema: long term beneficts/risk of preventive treatments with androgens.
Hereditary angioedema associated with a deficiency of C1 inhibitor may have diverse manifestations such as cutaneous edema, painful abdomen crises but also laryngeal edema that may have a lethal evolution.
Androgens have proven their preventive efficacy. Danazol (Danatrol®) decreases the frequency of crises by 90%, at a dose of 600 mg/day.
The study performed by Konrad Bork et al aimed at analysing the benefit/risk ration of long term preventive treatment (Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients. Annals of Allergy, Asthma and Immunology 2008, vol. 100, no. 2, pp. 153 – 161).
Patients were retrospectively studied and they had been treated for a period from 2 months to 30 years with androgens. Most of them (111/118) responded to treatment.
Nearly half of them no longer had any manifestations or only one episode per year.
For the remaining patients, the frequency of crises was decreased and their intensity was clearly lower than before treatment, whereas laryngeal edema decreased to 4.8%.
Secondary effects (weight gain, virilisation, menstrual irregularities, headaches, depression and/or hepatic adenomas) that lead to discontinuation of treatment were seen in 98/118 of patients.
In spite of these inconveniencies, the authors stress that compliance to Danazol remained good, given the therapeutic benefits that these patients can have when on the drug.
Omalizumab: kinetics of reactions upon treatment cessation or dose reduction
It has been well established that humanised recombinant anti-IgE antibodies rapidly reduce serum IgE concentration and simultaneously decreases the intensity of IgE- dependent respiratory manifestations.
But what happens once we suspend the treatment or reduce the doses ?
Corren J et al (Allergen skin tests and free IgE levels during reduction and cessation of omalizumab therapy - J Allergy Clin Immunol. 2008 Feb;121(2):506-11) attempted to answer this question.
With such a goal, 40 patients with perennial allergic rhinitis and who were on day 98 after beginning of treatment with Omalizumab, were randomised into two groups to receive two different doses of intravenous Omalizumab.
At a first stage, initial doses were respectively openly reduced by 0.015 or 0.030 mg/kg/IU/ml every 2 weeks for 28 weeks.
During the following 18 weeks, doses were again decreased, respectivement to 0.0015 or 0.0050 mg/kg/IU/mL, given at the same rhythm as before.
Results :
In comparison with levels before treatment, day 98 serum IgE concentrations were decreased by 96% to 99%, and the intensity of responses to skin tests were clearly less important.
At day 322, upon dose reduction, there was an increase in serum IgE, associated with an increase in the intensity of skin test responses, whereas at day 378, upon complete cessation of treatment, serum IgE and skin test reactivity had returned to their initial levels.
It should be noted that the suppressive action Omalizumab had on skin test reactivity was weaker among patients who initially had the lowest serum IgE levels.
In summary, Omalizumab-associated inhibitory effects on skin prick tests and serum IgE levels were not fully maintained during reduction of doses and were no longer observed upon treatment cessation. Therefore, efficacy of Omalizumab requires the maintenance of adequate doses that are established in function of the body mass and the initial serum IgE levels.
We thought that everything had been said about the controversial, protective role of breastfeeding against Allergy and Asthma, but its mode of action was not clear. Now, a group of French researchers from the Institut Pasteur and INSERM performed an experimental study in mice (Breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma :Valérie Verhasselt et coll. Nature Medicine 2008 14 170-175) and put forward a plausible explanation that made the journal Editorial comment : « We breathe better thanks to maternal milk ».
By exposing lactating mice to an aeroallergen, one can find the allergen in the milk, and this fact is associated with the development of tolerance to this allergen in the progeny .
Thus, allergen-specific tolerance develops by oral route, and which can subsequently protect the animal against allergies in the respiratory system.
Such tolerance is not mediated by Immunoglobulins, but by CD4+ T Lymphocytes CD4, and particularly depends upon Transforming Growth factor : TGF β, which can be found in these cells .
This finding may explain the efficacy of sublingual Immunotherapy, currently often used in Allergy and opens up new therapeutic perspectives.
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